Protein l-isoaspartyl methyltransferase (PIMT/PCMT1), a product of the human pcmt1 gene, catalyzes repair of abnormal l-isoaspartyl linkages in age-damaged proteins. Pcmt1 knock-out mice exhibit a profound neuropathology and die 30-60 days postnatal from an epileptic seizure. Here we express 15 reported variants of human PIMT and characterize them with regard to their enzymatic activity, thermal stability, and propensity to aggregation. One mutation, R36C, renders PIMT completely inactive, whereas two others, A7P and I58V, exhibit activity that is 80-100% higher than wild type. G175R is highly prone to aggregation and has greatly reduced activity. R17S and R17H show markedly enhanced sensitivity to thermal denaturation. Based on previous studies of moderate PIMT variation in humans and mice, we predict that heterozygosity for R36C, G175R, R17S, and R17H will prove detrimental to cognitive function and successful aging, whereas homozygosity (if it ever occurs) will lead to severe neurological problems in the young.

Purpose

To estimate the effectiveness of a multimodal educational intervention to increase use of shared decision-making (SDM) behaviors by inpatient pediatric and internal medicine hospitalists and trainees at teaching hospitals at Stanford University and the University of California, San Francisco.

Method

The 8-week Patient Engagement Project Study intervention, delivered at four services between November 2014 and January 2015, included workshops, campaign messaging, report cards, and coaching. For 12-week pre- and postintervention periods, clinician peers used the nine-point Rochester Participatory Decision-Making Scale (RPAD) to evaluate rounding teams' SDM behaviors with patients during ward rounds. Eligible teams included a hospitalist and at least one trainee (resident, intern, medical student), in addition to nonphysicians. Random-effects models were used to estimate intervention effects based on RPAD scores that sum points on nine SDM behaviors per patient encounter.

Results

In total, 527 patient encounters were scored during 175 rounds led by 49 hospitalists. Patient and team characteristics were similar across pre- and postintervention periods. Improvement was observed on all nine SDM behaviors. Adjusted for the hierarchical study design and covariates, the mean RPAD score improvement was 1.68 points (95% CI, 1.33-2.03; P < .001; Cohen d = 0.82), with intervention effects ranging from 0.7 to 2.5 points per service. Improvements were associated with longer patient encounters and a higher percentage of trainees per team.

Conclusions

The intervention increased behaviors supporting SDM during ward rounds on four independent services. The findings recommend use of clinician-focused interventions to promote SDM adoption in the inpatient setting.

Alzheimer's disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 - a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses - in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins - including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) - and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aβ and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD.